Defective removal of invariant chain peptides from MHC class II suppresses tumor antigen presentation and promotes tumor growth

被引:0
|
作者
Bandola-Simon, Joanna [1 ]
Ito, Yoshinaga [2 ]
Wucherpfennig, Kai W. [3 ,4 ,5 ,6 ]
Roche, Paul A. [1 ]
机构
[1] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA
[2] Kyoto Univ, Inst Life & Med Sci, Kyoto 6068507, Japan
[3] Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02215 USA
[4] Harvard Med Sch, Dept Immunol, Boston, MA 02115 USA
[5] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA
[6] Harvard Med Sch, Boston, MA 02115 USA
来源
CELL REPORTS | 2025年 / 44卷 / 01期
基金
美国国家卫生研究院;
关键词
HLA-DR MOLECULES; COMPLEX CLASS-II; T-CELL HELP; DENDRITIC CELLS; DOWN-REGULATION; MELANOMA LESIONS; CATHEPSIN-S; CLIP; EXPRESSION; DM;
D O I
10.1016/j.celrep.2024.115150
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tumor-draining lymph node dendritic cells (DCs) are poor stimulators of tumor antigen-specific CD4 T cells; however, the mechanism behind this defect is unclear. We now show that, in tumor-draining lymph node DCs, a large proportion of major histocompatibility complex class II (MHC-II) molecules retains the class II-associated invariant chain peptide (CLIP) fragment of the invariant chain bound to the MHC-II peptide binding groove due to reduced expression of the peptide editor H2-M and enhanced activity of the CLIP-generating proteinase cathepsin S. The net effect of this is that MHC-II molecules are unable to efficiently bind antigenic peptides. DCs in mice expressing a mutation in the invariant chain sequence that results in enhanced MHC-IICLIP accumulation are poor stimulators of CD4 T cells and have diminished anti-tumor responses. Our data reveal a previously unknown mechanism of immune evasion in which enhanced expression of MHC-II-CLIP complexes on tumor-draining lymph node DCs limits MHC-II availability for tumor peptides.
引用
收藏
页数:15
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